1. Field of the Invention
This invention relates to disubstituted N-aralkyl piperidine derivatives useful as antipsychotic agents and pharmaceutical compositions containing them. Furthermore, this invention relates to methods of using these compounds in the treatment of physiological or drug induced psychosis or dyskinesia in a mammal.
2. Prior Art
U.S. Pat. No. 4,876,262 (Oinuma et al.) describes antiarrhythmic agents having the formula: ##STR1## wherein: R.sub.1 is lower alkyl or tolyl;
R.sub.2 is H, hydroxyl, lower alkoxy or lower alkyl; PA1 R.sub.3 is H, lower alkyl, lower alkenyl, cycloalkyl or cycloalkylalkyl, PA1 X is --CO--, --CH.sub.2 -- or --CHOH--; PA1 g and h independently are 1-3, with the proviso that g+h is 3 or 4; and PA1 Y is --A--B, PA1 wherein B is: ##STR2## wherein R.sup.6 is H, lower alkyl, lower alkoxy, cyano, imidazolyl, hydroxyl or halogen]. PA1 ALK is lower alkylene radical; and PA1 Ar is aryl or heteroaryl. PA1 A is CO, CHOH or CH.sub.2. PA1 n is 2-4. PA1 R.sup.1 is H or halogen. PA1 R.sub.2 and R.sub.4 independently are H, alkyl of 1 to 3 carbon atoms; PA1 CR.sub.1 R.sub.2 or CR.sub.3 R.sub.4 may be C.dbd.O provided that both cannot be C.dbd.O; PA1 Ar, Ar' and Ar" independently are phenyl optionally substituted with 1-5 substituents independently selected from the group consisting of: PA1 R.sub.5 to R.sub.14 independently are H or alkyl of 1-3 carbon atoms; PA1 m and n independently are 1-5; and PA1 p is 1-2, provided that except as noted above, all other positions on the piperidine ring are substituted by H. PA1 m plus n is 2 or 3; and/or PA1 p is 1-2; and/or PA1 Ar and Ar' independently are phenyl optionally substituted with 1-3 substituents as listed above or naphthyl, pyridyl, pyrimidyl, quinolinyl or indolyl. PA1 (a) 1-Benzyl-4-(2'-(4"-fluorophenyl)-2'-hydroxy ethyl) piperidine or the hydrochloride salt thereof; PA1 (b) 1-Benzyl-4-(2'-(4"-fluorophenyl)-2'-oxoethyl) piperidine or the maleate salt thereof; PA1 (c) 1-Benzyl-4-(2'-(4"-fluorophenyl)-1'-oxoethyl) piperidine, or the maleate salt thereof; PA1 (d) 1-(4'-Pyridylmethyl)-4-(2'(4"-fluorophenyl)-1'-oxoethyl)piperidine, or the maleate salt thereof.
[wherein A is: --(CH.sub.2).sub.n (n=1-5), straight chain C.sub.1-5 alkylene and substituted with lower alkyl, phenyl or hydroxyl, straight chain C2-5 alkenylene, --(CH.sub.2).sub.k --S-- (k=2-5), or --(CH.sub.2).sub.P CO (p=1-4), and PA2 C1-4 alkyl sulfonyl, C1-5 alkyl carbonyl or aroyl; and PA2 H, halogen, OH, alkoxy of 1-3 carbon atoms, NR.sub.10 R.sub.11, SH, S(O).sub.t R.sub.12 (t=0-2), haloalkyl of 1-3 carbon atoms and 1-7 halogen atoms, alkyl of 1-3 carbon atoms, CO.sub.2 H, carboalkoxy of 2-6 carbon atoms, CO.sub.2 NR.sub.13 R.sub.14, CN, NO.sub.2, SO.sub.2 NH.sub.2 or SO.sub.3 H, PA2 or Ar, Ar' and Ar" independently are naphthyl, pyridyl, pyrimidyl, quinolinyl, isoquinolinyl, indolyl or indazolyl each optionally substituted by H, halogen or alkyl of 1 to 3 carbons;
U.S. Pat. No. 4,254,127 (Vandenberk et al.) describe in pertinent part compounds of the formula: ##STR3## wherein: X is C.dbd.O, CHOH, CHO Acyl, CH.sub.2, C(O alkyl).sub.2 ;
These compounds are described as having potent serotonin-antagonistic and strong psychotropic activity and as being useful in the treatment of mental disorders and congestive diseases and as antiemetics.
U.S. Pat. No. 4,294,841 (Champseix et al.) describes antiarrhythmic, antidepressant and anxiolytic compounds of the formula: ##STR4## wherein: X and Y independently are H, halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, CF.sub.3, OH, NH.sub.2, C1-4 monoalkylamino or amino groups substituted by one of the following:
EP 0,208,235 (Carr et al.) describes selective serotonin antagonist compounds of the formula: ##STR5## wherein: R.sup.1 -R.sup.4 independently are H, C1-C6 alkyl, halogen, CF.sub.3, OH, C1-C6 alkoxy or amino; and
U.S. Pat. No. 4,283,404 (Carr et al.) describes antipsychotic agents which act due to dopamine antagonism, having the formula: ##STR6## wherein: R is H, alkyl, alkoxy, halogen or CF.sub.3 ; and
Nagai et al., Chem. Pharm. Bull., 27 (5) 1159-1168 (1979) describe the synthesis of 1-substituted 2-[2-(p-fluorobenzoyl)ethyl]piperidine and related compounds. Related compounds include but are not limited to 1-ethyl-3-(p-fluorophenacyl) piperidine and 1-[3-(p-fluorobenzoyl)propyl]-3-(p-fluorophenacyl) pyrrolidine and 4-(p-fluorobenzoyl) piperidines which have CNS-depressing activities.
Unlike the prior art compounds, the compounds of the present invention are potent antipsychotic compounds which exert their effect through selective sigma receptor antagonism.
Traditionally, antipsychotic agents such as the phenothiazines and butyrophenones are potent dopamine receptor antagonists which are associated with a high incidence of side effects, particularly Parkinson-like motor movements or extra-pyramidal side effects (EPS) and dyskinesias including tardive dyskinesia at high doses. Many of these side effects are not reversible even after the dopamine receptor antagonist agent is discontinued.
The present invention relates to antipsychotic agents which act by selective antagonism of the sigma receptor rather than antagonism to the dopamine receptor. The present compounds therefore have a low potential for the typical movement disorders associated with known antipsychotic agents, while maintaining the ability to antagonize aggressive behavior and hallucinogenic-induced behavior and therefore are useful as antipsychotic and dyskinetic agents.